(1) Field of the Invention
The chemical processes of the present invention produce novel antibacterial agents of the .beta.-lactam type containing a hitherto unknown nucleus and useful intermediates for their synthesis.
(2) Description of the Prior Art
Penicillins and cephalosporins comprise a group of well-known antibacterial agents commonly grouped together as a class called .beta.-lactam antibiotics. For a recent review of this field with many citations (especially the first ten) to the prior work, see J. P. Hou and J. W. Poole, .beta.-lactam Antibiotics: Their Physiocochemical Properties and Biological Activities in Relation to Structure, J. Pharmaceutical Sciences, 60(4), 503-532 (April, 1971). Most of the work in this field has fundamentally been done, speaking broadly, with 6-aminopenicillanic acid, 7-aminocephalosporanic acid and derivatives thereof produced by fermentation or chemical transformation of the natural products. Despite the extensive progress made in preparing active derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid, there is a continuing search for synthetic and semi-synthetic routes to new families of .beta.-lactam antibiotics which may possess more advantageous properties then those derived from the known pencillin and cephalosporin nuclei.
Considerable work has been done on total chemical synthesis of both known .beta.-lactams and nuclear analogs of such known compounds. A recent review is the text by M. S. Manhas and A. K. Bose, Synthesis of Penicillin, Cephalosporin C and Analogues, Marcel Decker, Inc., 95 Madison Avenue, New York, N.Y., 1969. Another extensive review is by R. B. Morin and B. G. Jackson, Chemistry of Cephalosporin Antibiotics, Fortschr. Chem. Org. Naturst., 28, 343-403 (1970), especially pages 379-393; the now famous "Woodward Intermediate" is shown therein as compound 146 on page 387. A more recent review of .beta.-lactams is that by M. S. Manhas and A. K. Bose, Beta-Lactams: Natural and Synthetic: Part 1, Wiley-Interscience, New York, N.Y., 1971. A still further review article on the synthesis of .beta.-lactams is that by A. K. Kokerjee et al., Synthesis, 327 (1973).
Other pertinent publications relating to synthesis of .beta.-lactams are:
(a) D. M. Brunwin, G. Lowe and J. Parker, J.C.S. Chem. Comm., 1971, 865-867, describing synthesis of nuclear analogs of the penicillin-cephalosporin group.
(b) D. M. Brunwin et al., J. Chem. Soc. (C), 1971, 3756-3762 and J.C.S. Chem. Comm., 1972, 589-590 describing total synthesis of nuclear analogs of penicillins and cephalosporins.
(c) S. Kukolja, J. Amer. Chem. Soc., 93, 6267-6270 (1971) and 94, 7590-7593 (1972) describing preparation of 6-phthalimido-5-epipenicillanates and disulfide analogs of penicillins.
(d) J. A. Webber et al., J. Medicinal Chemistry, 14(11), 1136-1138 (1971) describing preparation of 3-cyanomethyl cephem nucleus.
(e) West German Patent Specification No. 2,219,601 (Farmdoc 76,051T) describing synthesis of .beta.-lactams of the formula ##STR2## wherein X is halo, N.sub.3 -- or H.sub.2 N--, A is --S--, --S--CH.sub.2 --, --O--, --O--CH.sub.2 --, --CH.sub.2, --CH.sub.2 CH.sub.2 -- or --NH-- and R.sup.1, R.sup.2 and R.sup.3 are hydrogen, C.sub.1 -C.sub.6 alkyl or aryl.
(f) U.K. Pat. No. 1,308,822 disclosing .beta.-lactams of the formula ##STR3## where Y=amino or substituted amino.
(g) S. Wolfe et al., Can. J. Chem., 50, 2894-2905 (1972) describing synthesis of sulfur-free penicillin derivatives.
(h) French Pat. No. 2,111,859 describing nuclei of the formula ##STR4## and 7-acrylated derivatives thereof.
(i) Helvetica Chimica Acta, 55(2), 388-429 (1972) describing nuclear modified cephalosporins and penicillins.
(j) F. Moll et al., Zeit. fur Naturforsch. B, 27(b)6, 727 (1972) describing nuclear analogs of cephalosporins.
(k) U.K. Specifications Nos. 1,271,013 and 1,271,014 describing .gamma.-lactams of 7-(acylamino)-3-aminomethyl-ceph-3-em-4-carboxylic acids.
(l) U.K. Specification No. 1,271,180 describing preparation of novel thiazoline azetidinone rearrangement products useful as intermediates in penicillin and cephalosporin synthesis.
(m) German Patent Specifications Nos. 2,046,822, 2,046,823 and 2,046,824 describing synthesis of novel azetidinone intermediates.
(p) G. Lowe et al., J. Chem. Soc. Perkins I, 1322 (1973) describing total synthesis of nuclear analogs of 7-methylcephalosporins having the formula ##STR5##
(o) D. M. Brunwin et al., J. Chem. Soc. Chem. Comm., 865 (1971) describing synthesis of compounds of the formula ##STR6##
(p) S. Wolfe et al., Canadian J. Chem., 50, 2902 (1972) describing compounds of the formula ##STR7##
(q) J. P. Luttringer et al., Tetrahedron Letters, 4163-4166 (1973) describing compounds of the formula ##STR8##
(r) U.S. Pat. No. 3,835,130 disclosing .beta.-lactams of the formula ##STR9## wherein R.sub.a and R.sub.b are each hydrogen or R.sub.a and R.sub.b form a covalent carbon-to-carbon bond, R.sub.1 ' represents hydrogen, R.sub.1 " is cyanoacetyl, bromacetyl or an acyl group of the formula ##STR10## in which Ar is phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl, R.sub.2 ' is hydrogen and R.sub.3 ' is hydrogen or lower alkyl.
(s) West German Offenlegungsschrift No. 2,355,209 describing synthesis of .beta.-lactams of the formula ##STR11## wherein R is acyl, A' is hydrogen, hydroxy, carbamoyloxy, thiocarbamoyloxy, quaternary ammonium, N-lower alkyl carbamoyloxy, N,N-di-lower alkyl carbamoyloxy, N-lower alkylthio and N,N-diloweralkylthiocarbamoyloxy, azido, halo, cyano, a tertiary amine, acyloxy, or a 5-member heterocyclic thio group having 1-4 hetero atoms; B is H, OCH.sub.3 or SR where R is lower alkyl or aryl; X is a divalent radical selected from --O--, --CH.sub.2 -- or --NY-- where Y is hydrogen, lower alkyl, formyl or benzyl and R' is hydrogen or a protecting group.